Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome.

Loss-of-function mutation of ABCC9, the gene encoding the SUR2 subunit of ATP sensitive-potassium (KATP) channels, was recently associated with autosomal recessive ABCC9-related intellectual disability and myopathy syndrome (AIMS). Here we identify nine additional subjects, from seven unrelated families, harbouring different homozygous loss-of-function variants in ABCC9 and presenting with a conserved range of clinical features. All variants are predicted to result in severe truncations or in-frame deletions within SUR2, leading to the generation of non-functional SUR2-dependent KATP channels. Affected individuals show psychomotor delay and intellectual disability of variable severity, microcephaly, corpus callosum and white matter abnormalities, seizures, spasticity, short stature, muscle fatigability and weakness. Heterozygous parents do not show any conserved clinical pathology but report multiple incidences of intra-uterine fetal death, which were also observed in an eighth family included in this study. In vivo studies of abcc9 loss-of-function in zebrafish revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility. Our findings define an ABCC9 loss-of-function-related phenotype, expanding the genotypic and phenotypic spectrum of AIMS and reveal novel human pathologies arising from KATP channel dysfunction.

[Invasive pneumoccal disease in children in Oslo 1998-2004]. / Invasiv pneumokokkinfeksjon hos barn i Oslo 1998-2004.

BACKGROUND: Invasive pneumococcal disease (IPD) is an important cause of morbidity and mortality in Norwegian children. MATERIAL AND METHODS: This retrospective study included all children (under 16 years) with isolates of Streptococcus pneumoniae from a normally sterile site admitted to the Department of Paediatrics at Ullevaal University Hospital in the period 1998 to 2004. We studied the epidemiology, predisposing factors, clinical picture, antimicrobial resistance, outcome of IPD and the theoretical coverage of the 7-valent conjugate pneumococcal vaccine (PCV7) in these children. The isolates were tested for antimicrobial susceptibility, serogrouped and serotyped. RESULTS: 68 children were identified; 31 of them had one or more predisposing factors. Six children died, all of them had a predisposing factor. Six of the seven children who survived with sequelae were previously healthy. 67 of 68 isolates were fully susceptible to benzyl penicillin and 13 isolates showed intermediate susceptibility or resistance to erythromycin. Serogroups or serotypes were obtained in 66 children. 24 (36.8%) children fulfilled the criteria for PCV7. 35 (51.1%) children had serotypes covered by the vaccine. Only 12 (17.6%) fulfilled the criteria for PCV7 and had serotypes covered by it. Four of the six children who died had serotypes covered by PCV7. INTERPRETATION: Invasive pneumococcal disease is a serious condition in children and vaccination can prevent disease in many children.